Structural modification of an orally active thrombin inhibitor, LB30057: Replacement of the D-pocket-binding naphthyl moiety

被引：30

作者：

Lee, K ^{[1
]}

Hwang, SY ^{[1
]}

Hong, S ^{[1
]}

Hong, CY ^{[1
]}

Lee, CS ^{[1
]}

Shin, Y ^{[1
]}

Kim, S ^{[1
]}

Yun, M ^{[1
]}

Yoo, YJ ^{[1
]}

Kang, M ^{[1
]}

Oh, YS ^{[1
]}

机构：

[1] LG Chem Ltd, Biotech Res Inst, Taejon 305380, South Korea

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 1998年 / 6卷 / 06期

关键词：

thrombin; inhibitor; oral; selective; amidrazone;

D O I：

10.1016/S0968-0896(98)00044-3

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

An amidrazonophenylalanine derivative LB30057 (2) was identified as a potent (K-i = 0.38 nM), selective, and orally active thrombin inhibitor. As a continuation of studies into benzamidrazone-based thrombin inhibitors, we have structurally modified compound 2 by replacing the naphthyl group with a variety of hydrophobic moieties. This study led to discovery of several compounds with significantly enhanced potency in thrombin inhibition without sacrificing selectivity against trypsin and oral absorption. The highest activity was obtained with compound 23 (K-i = 0.045 nM). (C) 1998 Elsevier Science Ltd. All rights reserved.

引用

页码：869 / 876

页数：8

共 32 条

[1]

BANNER D, 1993, PERSPECTIVES MED CHE, P27

[2] Potent thrombin inhibitors that probe the S-1' subsite: Tripeptide transition state analogues based on a heterocycle-activated carbonyl group [J].

Costanzo, MJ ;

Maryanoff, BE ;

Hecker, LR ;

Schott, MR ;

Yabut, SC ;

Zhang, HC ;

AndradeGordon, P ;

Kauffman, JA ;

Lewis, JM ;

Krishnan, R ;

Tulinsky, A .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (16) :3039-3043

[3] THROMBIN ACTIVE-SITE INHIBITORS [J].

DAS, J ;

KIMBALL, SD .

BIOORGANIC & MEDICINAL CHEMISTRY, 1995, 3 (08) :999-1007

[4] THE DETERMINATION OF ENZYME INHIBITOR CONSTANTS [J].

DIXON, M .

BIOCHEMICAL JOURNAL, 1953, 55 (01) :170-171

[5] Thrombin and factor Xa inhibition [J].

Edmunds, JJ ;

Rapundalo, ST ;

Siddiqui, MA .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 31, 1996, 31 :51-60

[6] Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position [J].

Feng, DM ;

Gardell, SJ ;

Lewis, SD ;

Bock, MG ;

Chen, ZG ;

Freidinger, RM ;

NaylorOlsen, AM ;

Ramjit, HG ;

Woltmann, R ;

Baskin, EP ;

Lynch, JJ ;

Lucas, R ;

Shafer, JA ;

Dancheck, KB ;

Chen, IW ;

Mao, SS ;

Krueger, JA ;

Hare, TR ;

Mulichak, AM ;

Vacca, JP .

JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (23) :3726-3733

[7] SELECTIVE KAPPA-OPIOID AGONISTS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF PIPERIDINES INCORPORATING AN OXO-CONTAINING ACYL GROUP [J].

GIARDINA, G ;

CLARKE, GD ;

DONDIO, G ;

PETRONE, G ;

SBACCHI, M ;

VECCHIETTI, V .

JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (21) :3482-3491

[8] PHARMACOLOGY OF SYNTHETIC THROMBIN INHIBITORS OF THE TRIPEPTIDE TYPE [J].

KAISER, B ;

HAUPTMANN, J .

CARDIOVASCULAR DRUG REVIEWS, 1992, 10 (01) :71-87

[9] THROMBIN INHIBITORS .2. AMIDE DERIVATIVES OF N-ALPHA-SUBSTITUTED L-ARGININE [J].

KIKUMOTO, R ;

TAMAO, Y ;

OHKUBO, K ;

TEZUKA, T ;

TONOMURA, S ;

OKAMOTO, S ;

FUNAHARA, Y ;

HIJIKATA, A .

JOURNAL OF MEDICINAL CHEMISTRY, 1980, 23 (08) :830-836

[10] THROMBIN INHIBITORS .3. CARBOXYL-CONTAINING AMIDE DERIVATIVES OF N-ALPHA-SUBSTITUTED L-ARGININE [J].